The proposed research combines modeling at molecular, cellular and network scales to address the mechanisms underlying a fundamental behavioral state: attention. Voluntary attention is essential for sensory- guided behavior and memory formation. The neurotransmitter Acetylcholine (ACh) is considered an important contributor to attentional modulation in the cortex. This project aims to understand how the spatio- temporally diffuse ACh system in the cortex achieves spatial and temporal specificity demanded by behavioral tasks such as attention. The studies outlined in this research will broadly aim to test the hypothesis that the cholinergic system achieves the required spatio-temporal precision by coordinating the expression and localization of its molecular components (enzymes, receptors, transporters) rather than the 'classical' approach of precise wiring with fast synaptic transmission. The mentored phase will involve examining how the anatomical organization of the cholinergic system in the cortex shapes the spatio-temporal profile of its transmission. Current models of cholinergic transmission have been implicitly guided by the knowledge of ACh machinery, especially that of enzymatic action, at the neuromuscular junction. Molecular-level models of reaction-diffusion systems will be used to test how the available enzymes in the cortical extracellular space shape the temporal profile of ACh released from non-synaptic sites. The project will aim to generate predictions for the spatial organization of the cholinergic system in the cortical ultra-structure. Inspired by previous work by the candidate, the computational principles guiding the modulatory role of sub-cellular domains of ACh receptors will be investigated in the independent phase. The candidate will use biophysical models of dendrites, ion channels and neurotransmitter receptors for these investigations. The progress made in the mentored and early independent phase will lead to investigation of the mechanisms of cholinergic modulation of network dynamics. Detailed biophysical and phenomenological network models will be used to explore the hypothesis that the known cell-type specificity and sub-cellular patterns of AChR expression in the primary visual cortex underlie the attention-modulation of network oscillations. To achieve these aims the candidate needs further training, specifically in advanced molecular modeling techniques and theoretical foundations of visual and molecular neurobiology. The mentoring lab and the present institute is the ideal training environment for the achievement of these goals. The candidate's mentor is one of the world's pioneers in the computational investigation of neurobiology. The neurobiology division at the institute has a strong focus on vision research. The candidate's main collaborator is one of the leading experts in the cholinergic system in the visual cortex. After a short period n this exciting environment, the candidate expects to be ready to embark upon an independent research career and will seek a tenure-track position in Neuroscience.